The therapeutic mechanism of action of antidepressant medications in humans remains unknown. Comparison of effects on specific neurotransmitters and their metabolites in cerebrospinal fluid (CSF), plasma and urine in the same patients continues and is complemented by physiologic, behavioral and neuroendocrine measures, allowing for clearer systems interpretations of changes. Recent findings of particular interest include the following: 1. We have identified unique biochemical changes in patients treated with electroconvulsive therapy (ECT) compared to antidepressant drugs. Although all active antidepressant treatments we have studied reduce norepinephrine (NE) turnover, only ECT increases CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin and homovanillic acid (HVA), the main dopamine metabolite. 2. Building upon our findings of common noradrenergic effects of biochemically disparate antidepressant treatments, we have investigated the relationships among various neurotransmitter systems in depressed patients before and after treatment. Characteristic patterns of changes not only in absolute but also relative concentrations of transmitter substances, e.g. HVA/5-HIAA ratio in CSF, are emerging in response to various interventions. 3. Several types of antidepressant drugs increase excretion of 6-hydroxymelatonin. Opposite results with the monoamine oxidase (MAO) inhibitor, clorgyline, in some patients, are consistent with the melatonin measure's relating to peripheral, rather than central, sympathetic nervous system activity. 4. Utilizing intravenous clomipramine in single doses small enough to maintain selective serotonin reuptake inhibition, diminished serotonergic function in depression, as reflected in blunted serum prolactin response, is seen in a preliminary comparison of patients and healthy volunteers.